The studies in rats proposed in this project will establish proof-of- concept and will aid in the selection of the human monoclonal anti-cocaine antibody which is the most promising for the eventual advancement to phase 1 clinical trials in human subjects. The criteria which will be used to define the leading candidate will be that human monoclonal anti-cocaine antibody which at the lowest concentration abolishes the self- administration by rats of a previously reinforcing dose of cocaine. A pivotal issue regarding the dose of antibody required to be clinically effective will be addressed by this project. The clinical effectiveness of passive immunotherapy is hypothesized to be due to the antibody-induced reduction of cocaine entry into the brain. Calculations based on hypothesis of the mechanism of action of immunotherapy indicate the expected properties and doses of monoclonal anti-cocaine antibodies which should be clinically effective. However, a previously published study reported that 10 fold lower doses of a monoclonal anti-cocaine antibody were effective in animal models of cocaine addiction. The dose of monoclonal antibody required for immunotherapy will determine how much antibody will be manufactured and thereby will determine the cost and the time frame of the entire SPIRCAP program. A commercially available mouse monoclonal anti-cocaine antibody has been characterized by Dr. Ball (Project 1). This antibody has high affinity and specificity for cocaine and is predicted to represent the standard by which human monoclonal anti- cocaine antibodies will be compared for efficacy. As human monoclonal anti-cocaine antibodies of appropriate specificity and affinity are generated from project 1, the leading candidate antibodies will undergo testing in rats to determine: 1) The pharmacokinetics of the human monoclonal anti-cocaine antibodies. 2) The dose of antibody required to abolish the self-administration of cocaine and to attenuate the effects of cocaine on locomotor behavior and stereotype. 3) The pharmacokinetics of cocaine and the entry of cocaine into the brain in the presence of the antibody. Measurements of antibody levels and cocaine plasma concentrations will be provided by the clinical chemistry Core (Scientific Core 2). The pharmacokinetic data will be generated and analyzed in collaboration with the pharmacokinetics group (Scientific Core 4). These data will determine the quantity of antibody required and which antibody will be advanced for scale-up production and in good manufacturing practice (GMP) certified facility and then to animal toxicity testing under the auspices of the Medications Development Division of NIDA.